rs1804495

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000354.6(SERPINA7):c.909G>T(p.Leu303Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,204,797 control chromosomes in the GnomAD database, including 7,019 homozygotes. There are 52,359 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.12 ( 616 hom., 3967 hem., cov: 23)

Exomes 𝑓: 0.13 ( 6403 hom. 48392 hem. )

Consequence

SERPINA7
NM_000354.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:2B:6

Conservation

PhyloP100: -1.06

Publications

38 publications found

Variant links:

Genes affected

SERPINA7 (HGNC:11583): (serpin family A member 7) There are three proteins including thyroxine-binding globulin (TBG), transthyretin and albumin responsible for carrying the thyroid hormones thyroxine (T4) and 3,5,3'-triiodothyronine (T3) in the bloodstream. This gene encodes the major thyroid hormone transport protein, TBG, in serum. It belongs to the serpin family in genomics, but the protein has no inhibitory function like many other members of the serpin family. Mutations in this gene result in TGB deficiency, which has been classified as partial deficiency, complete deficiency, and excess, based on the level of serum TBG. Alternatively spliced transcript variants encoding different isoforms have been found, but the full-length nature of these variants has not been determined.[provided by RefSeq, Jun 2012]

SERPINA7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003224343).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.277 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SERPINA7	NM_000354.6 link	c.909G>T	p.Leu303Phe	missense_variant	Exon 4 of 5	ENST00000372563.2	NP_000345.2
SERPINA7	XM_006724683.3 link	c.909G>T	p.Leu303Phe	missense_variant	Exon 4 of 5		XP_006724746.1
SERPINA7	XM_005262180.5 link	c.909G>T	p.Leu303Phe	missense_variant	Exon 4 of 5		XP_005262237.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SERPINA7	ENST00000372563.2 link	c.909G>T	p.Leu303Phe	missense_variant	Exon 4 of 5	5	NM_000354.6	ENSP00000361644.1
SERPINA7	ENST00000327674.8 link	c.909G>T	p.Leu303Phe	missense_variant	Exon 3 of 4	1		ENSP00000329374.4
SERPINA7	ENST00000487487.1 link	n.182G>T		non_coding_transcript_exon_variant	Exon 2 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.122

AC:

13603

AN:

111367

Hom.:

618

Cov.:

show subpopulations

Gnomad AFR

AF:

0.119

Gnomad AMI

AF:

0.308

Gnomad AMR

AF:

0.102

Gnomad ASJ

AF:

0.146

Gnomad EAS

AF:

0.236

Gnomad SAS

AF:

0.295

Gnomad FIN

AF:

0.0788

Gnomad MID

AF:

0.158

Gnomad NFE

AF:

0.114

Gnomad OTH

AF:

0.112

GnomAD2 exomes

AF:

0.142

AC:

25859

AN:

182266

AF XY:

0.150

show subpopulations

Gnomad AFR exome

AF:

0.119

Gnomad AMR exome

AF:

0.107

Gnomad ASJ exome

AF:

0.154

Gnomad EAS exome

AF:

0.248

Gnomad FIN exome

AF:

0.0852

Gnomad NFE exome

AF:

0.116

Gnomad OTH exome

AF:

0.122

GnomAD4 exome

AF:

0.128

AC:

140495

AN:

1093377

Hom.:

6403

Cov.:

AF XY:

0.135

AC XY:

48392

AN XY:

359617

show subpopulations

African (AFR)

AF:

0.115

AC:

3034

AN:

26281

American (AMR)

AF:

0.109

AC:

3825

AN:

35109

Ashkenazi Jewish (ASJ)

AF:

0.151

AC:

2920

AN:

19322

East Asian (EAS)

AF:

0.196

AC:

5898

AN:

30159

South Asian (SAS)

AF:

0.287

AC:

15514

AN:

54021

European-Finnish (FIN)

AF:

0.0907

AC:

3676

AN:

40511

Middle Eastern (MID)

AF:

0.151

AC:

623

AN:

4124

European-Non Finnish (NFE)

AF:

0.118

AC:

98593

AN:

837961

Other (OTH)

AF:

0.140

AC:

6412

AN:

45889

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

3938

7875

11813

15750

19688

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3908

7816

11724

15632

19540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.122

AC:

13601

AN:

111420

Hom.:

616

Cov.:

AF XY:

0.118

AC XY:

3967

AN XY:

33688

show subpopulations

African (AFR)

AF:

0.118

AC:

3633

AN:

30666

American (AMR)

AF:

0.103

AC:

1083

AN:

10548

Ashkenazi Jewish (ASJ)

AF:

0.146

AC:

385

AN:

2632

East Asian (EAS)

AF:

0.236

AC:

811

AN:

3443

South Asian (SAS)

AF:

0.294

AC:

772

AN:

2625

European-Finnish (FIN)

AF:

0.0788

AC:

480

AN:

6091

Middle Eastern (MID)

AF:

0.151

AC:

AN:

212

European-Non Finnish (NFE)

AF:

0.114

AC:

6029

AN:

53008

Other (OTH)

AF:

0.111

AC:

168

AN:

1520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

437

874

1311

1748

2185

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

158

316

474

632

790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.120

Hom.:

12966

Bravo

AF:

0.124

TwinsUK

AF:

0.117

AC:

435

ALSPAC

AF:

0.118

AC:

341

ESP6500AA

AF:

0.123

AC:

472

ESP6500EA

AF:

0.112

AC:

751

ExAC

AF:

0.145

AC:

17641

EpiCase

AF:

0.115

EpiControl

AF:

0.121

ClinVar

Significance: Benign

Submissions summary: Pathogenic:2Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

SERPINA7-related disorder

Benign:2

Apr 24, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Nov 20, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 25, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 33554479, 2155256, 1515456, 25333069) -

Thyroxine-binding globulin, variant P

Pathogenic:1

Mar 01, 1992

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Thyroxine-binding globulin quantitative trait locus

Pathogenic:1

Department of Endocrinology, The Fourth Affiliated Hospital of Guangzhou Medical University

Significance:Likely risk allele

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

T;T

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.71

.;T

MetaRNN

Benign

0.0032

T;T

MetaSVM

Benign

-0.53

MutationAssessor

Pathogenic

3.4

M;M

PhyloP100

-1.1

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-3.3

D;D

REVEL

Uncertain

0.35

Sift

Uncertain

0.013

D;D

Sift4G

Uncertain

0.020

D;D

Polyphen

0.98

D;D

Vest4

0.17

MutPred

0.30

Gain of methylation at K298 (P = 0.093);Gain of methylation at K298 (P = 0.093);

MPC

0.15

ClinPred

0.068

GERP RS

2.5

Varity_R

0.82

gMVP

0.68

Mutation Taster

=70/30

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over